The proposed research is directed at several pathophysiological aspects of acute and chronic renal failure. 1) The pathogenesis of a model of reversible acute renal failure, induced by a single dose of endotoxin, will continue to be defined in rats. The initiating events and the factors responsible for the maintenance and the recovery phases will be studied using clearance, metabolic and micropuncture methodologies spectron/microscopy. 2) Continued definition of the functional adaptations that occur in chronic renal failure will be approached from the point of view of the biological control systems with particular emphasis on sodium, potassium and phosphorus homeostasis. For sodium and potassium the signal created by the ingestion of salt will be defined. For phosphorus, the role of parathyroid hormone in regulating phosphate balance and vitamin D metabolism will be studied in dogs. Conversely, the role of vitamin D metabolites and cimetidine, an H2 receptor inhibitor, on uremic hyperparathyroidism will be studied in dog and in man. Particular attention will be given of the underlying molecular mechanisms underlying the effects of cimetidine on the calcium-phosphorus-parathormone-vitamin D axis.